Ruthenium catalysts and their use in the asymmetric hydrogenation of cyclopentenones

ABSTRACT

A catalyst of ruthenium (II) which includes bidentate phosphine ligands. The catalyst is obtainable by a process which includes the steps of treating equimolar amounts of an appropriate Ru(II) complex and a bidentate diphosphine ligand with an acid of formula HX, wherein X is a non-coordinating anion. The acid is used in a ratio which does not exceed 2 molar equivalents per mole of Ru(II) complex and the treatment is carried out in a non-coordinating or weakly coordinating solvent and under an inert atmosphere. This catalyst is useful for the preparation of the preferred isomer of HEDIONE, having the (+)-(1R)-cis-configuration.

TECHNICAL FIELD

The present invention relates to the field of asymmetric hydrogenationin homogeneous conditions and, more particularly, to the use of novelRu(II) chiral catalysts for the asymmetric hydrogenation ofcyclopentenone derivatives having the general formula ##STR1## whereinR¹ represents a linear or branched C₁ to C₄ alkyl radical and R²represents a saturated or unsaturated, linear or branched, C₁ to C₈hydrocarbon radical.

The compounds of formula (II) are substrates the asymmetric andstereospecific hydrogenation of which had proved heretofore impossibleas a result of their weak donor capability and of their hinderedstructure, and this in spite of all the progress in homogeneouscatalysis achieved in recent years.

PRIOR ART

A great number of chiral catalysts useful for asymmetric hydrogenationsis in fact known at present. In the context of the present invention, wecan cite in particular the efforts of two research groups which activelystudied the synthesis of Ru(II) chiral catalysts, obtained from theRu(II) complex of formula (COD)Ru(2-methylallyl)₂!(COD=cyclo-1,5-octadiene).

Thus, J.-P. Genet and his collaborators have published work related tocatalysts of formula Ru(P*--P*)(2-methylallyl)₂ !, wherein P*--P*represents a bidentate ligand of the type of those currently known underabbreviated designations such as DIOP, CHIRAPHOS, PROPHOS, BDPP, CBD,NORPHOS, DEGUPHOS, BPPM, BINAP, R-DuPHOS (R=methyl or ethyl), BIPHEMP oryet DIPAMP (see, for example, J.-P. Genet et al., Tetrahedron: Asymmetry1991, 2, 43). Such catalysts were obtained by heating theabove-mentioned Ru(II) complex together with the appropriate diphosphineligand, in a solvent such as hexane or toluene, such as to replace thecyclooctadiene with the chiral phosphine.

Upon subsequent work (see, for example, WO 91/02588; J.-P. Genet, AcrosOrganics Acta, 1994, 1, 1-8; J.-P. Genet et al., Tetrahedron :Asymmetry, 1994, 5, 665-690), these authors described the transformationof such catalysts via protonation by means of aqueous acids such as HBr,HCl, HF or HBF₄, in strongly coordinating solvents, capable of playing arole in stabilizing the coordination structure around the metal, whichstructure, according to the same authors, is of the hexacoordinate type.This kind of catalysts, which can be prepared in situ, proved to beuseful for the asymmetric hydrogenation, in protic or stronglyelectron-donating solvents (methanol, ethanol, THF, or their mixtureswith other solvents), of substrates comprising carbonyl groups andacyclic ethylenic bonds.

Other studies (see, for example, F. Heiser et al., Tetrahedron:Asymmetry, 1991, 2, 51-62; EP 643 052; EP 398 132; EP 570 674) haveresulted in reports of the use of catalysts prepared in situ forhydrogenating a variety of substrates, starting from the same rutheniumcomplex, but following a process according to which a mixture of saidcomplex and an appropriate diphosphine ligand is treated with namely CF₃COOH, once again in an electron-donor solvent able to stabilize thecoordinating structure of the metal.

These catalysts, and others obtained according to similar processesdescribed in the cited references, reveal themselves very efficient inthe asymmetric hydrogenation of various substrates, often goodelectron-donor substrates capable of coordinating the Ru(II), and aretypically used with protic solvents, or mixtures of protic and aproticsolvents. However, they proved to be inefficient with regard to thehydrogenation of substrates (II) cited above, when prepared according tothe prior art methods and used under the reported conditions. In fact,substrates (II) are weak electron-donors, when compared to the type ofsubstrates described in the prior art, and the many attempts carried outheretofore in an effort to asymmetrically hydrogenate them had alwaysproved fruitless.

It should be pointed out that, among the formula (II) substrates, methyl3-oxo-2-pentyl-1-cyclopentene-1-acetate is particularly interesting inthe context of the invention, inasmuch as its asymmetric hydrogenationcould potentially provide, in a single step, the optically activeisomers of methyl dihydrojasmonate or Hedione® (origin: Firmenich SA,Geneva, Switzerland), a prized perfuming ingredient.

Amongst the four possible Hedione® stereoisomers, methyl(+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate is known to possess attheir best the odor characters, and namely the jasmine note, for whichHedione® is prized, the strength of this isomer's odor being alsosuperior to that of the other isomers by several orders of magnitude.Therefore, the production of methyl(+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate in an optically purestate, or of isomer mixtures which contain essentially this isomer, isof capital importance in the fragrance industry. Yet, there is atpresent no synthesis of this compound which is susceptible of industrialapplication, starting from a substrate such as cited above, all effortsto asymmetrically hydrogenate said substrate having met with failure upuntil now.

DESCRIPTION OF THE INVENTION

The aim of the present invention is to provide precisely a solution tothis problem.

We have now discovered that this preferred isomer of Hedione® can beprepared in excellent diastereochemical and enantiomeric purity, by wayof a one-step process, resorting to the use of novel Ru(II) chiralcatalysts, produced by means of an original method.

An object of the present invention is therefore a ruthenium (II)catalyst comprising bidentate phosphine ligands, characterized in thatsaid catalyst is obtainable by a process which comprises treatingequimolar amounts of an appropriate Ru(II) complex and a bidentatediphosphine ligand with an acid of the formula HX, wherein X is anon-coordinating anion, said acid being used in a ratio which does notexceed 2 molar equivalents per mole of Ru(II) complex and the treatmentbeing carried out in a non-coordinating or weakly coordinating solventand under an inert atmosphere.

By an "appropriate Ru(II) complex" it is meant here any Ru(II) complexwherein the metal is surrounded by dienyl and alkyl type ligands, suchthat the metal is σ-bonded to two of said ligands, which ligands furtherpossess at least one bond π-bonded to the metal, two other metalcoordination positions being π-bonded to the same said two ligands or toa distinct ligand.

Several ruthenium compounds, or analogous compounds of other transitionmetals, are known from the prior art which comprise ligands fulfillingthe above-mentioned conditions and which are convenient as precursors ofthe catalysts of the present invention.

One can cite more particularly, as appropriate ruthenium(II) complexes,the compounds of the (diene)Ru(allyl)₂ ! type, wherein "diene" standsfor example for COD (cycloocta-1,5-diene) or NBD (norbornadiene), or yethepta-1,4-diene, and "allyl" represents a 2-propenyl or 2-methallylradical (see, for instance, J.-P. Genet et al., cited references; M. O.Albers et al., Inorganic Synth. 1989, 26, 249; R. R. Schrock et al., J.Chem. Soc. Dalton Trans, 1974, 951). Other appropriate ruthenium(II)complexes include the compounds of the bis(pentadienyl)Ru! type, wherein"pentadienyl" represents a 2,4-dimethylpentadienyl,2,3,4-trimethylpentadienyl, 2,4-di(tert-butyl) pentadienyl or yet2,4-dimethyl-1-oxapentadienyl radical (see, for example, R. D. Ernst etal., J. Organometallic Chem., 1991, 402, 17; L. Stahl et al.,Organometallic 1983, 2, 1229 ; T. Schmidt et al., J. Chem. Soc. Chem.Commun., 1991, 1427; T. D. Newbound et al., Organometallics, 1990, 9,2962).

Following a preferred embodiment of the catalysts of the invention,there is used as the Ru(II) precursor, the compound of formula(COD)Ru(2-methallyl)₂ !, the bis(2,4-dimethylpentadienyl)ruthenium (e.g.L. Stahl et al. or T. D. Newbound et al., refs cited) or thebis(2,4-dimethyl-1-oxapenta-dienyl)ruthenium complexes (e.g. T. Schmidtet al., ref. cited).

Among the bidentate phosphines which can be used as ligands in thecatalysts of the invention, there can be cited, as preferredembodiments, those selected from the group consisting of the chiralphosphines known under the abbreviations of Me-DuPHOS, Et-DuPHOS, BINAP,To1BINAP, SKEWPHOS, DIPAMP and CHIRAPHOS, the structures of which arerepresented hereafter for one of the enantiomers in particular: ##STR2##

Other chiral bidentate phosphines which can be used in the chiralcatalysts of the invention include for instance those known under thename of NORPHOS, or yet analogues of the DuPHOS type ligands, so-called"BPE", the structures of which are represented hereafter for one of theenantiomers. ##STR3##

Other particularly useful ligands for the preparation of the catalystsof the invention are the chiral diphosphines of formula: ##STR4## inparticular that known under the designation of (R)-(S)-JOSIPHOS(R=cyclohexyl, R'=phenyl) or (-)-JOSIPHOS.

Moreover, it has been ascertained that other ligands, chiral or achiral,can be used to prepare the catalysts according to the invention, whichcatalysts proved capable of catalyzing the hydrogenation of substrates(II) with a cis stereoselectivity above 80% and, in most cases, 95%. Tothis end, there can be cited the achiral or racemic bidentateferrocenyl-diphosphines such as represent hereafter: ##STR5##

Other bidentate phosphines useful as ligands are represented below:##STR6##

More generally, one can use as ligands in the catalysts of the inventionany bidentate diphosphine comprising substituent groups capable ofrendering said diphosphine sufficiently electron-rich to allow it tostabilize the metal, without however depriving said metal from itsability to coordinate substrate (II).

It has also been observed that the diphosphines having a certain numberof alkyl or cycloalkyl type substituents revealed themselvesparticularly useful for the aim of the invention and provided catalystswhich were very active and efficient for the hydrogenation of substrates(II).

It is apparent from the above that the preferred ligands for preparingthe catalysts of the invention are diphosphine ligands in which the twophosphorous atoms are bridged by groups of the alkyl, 1,2-benzenyl,bis(naphtalenyl) or yet 1,1'-ferrocenyl type, optionally substituted,said phosphorous atoms further carrying two other substituents, whichcan be identical or different and formed of alkyl, aryl or alkylarylradicals, or yet alicyclic radicals.

The catalysts of the invention which comprise diphosphine ligands of theDuPHOS, BINAP, To1BINAP, SKEWPHOS or JOSIPHOS type are particularlyadvantageous as catalysts for the asymmetric hydrogenation of thesubstrates of formula (II), as is apparent from the examples presentedfurther on.

Amongst the latter catalysts, those which comprise ligands of theSKEWPHOS, JOSIPHOS or Me-DuPHOS type showed themselves capable ofparticularly advantageous performances and are therefore preferredaccording to the invention. (R,R)-(-)-Me-DuPHOS, or(-)-1,2-bis(2,5-dimethylphospholano)benzenyl made it possible to obtainchoice catalysts according to the invention.

The ligands of the type L1 to L13 represented below are eithercommercially available compounds or they can be prepared according toprocesses analogous to previously described methods.

For example, the ligands of the DuPHOS, SKEWPHOS, BINAP, CHIRAPHOS,DIPAMP and NORPHOS type are mostly commercial products and, in anyevent, they can be obtained via processes described in the literature,namely in reference works such as the books of R. Noyori, AsymmetricCatalysis in Organic Synthesis, John Wiley & Sons, N.Y (1994), Chap. IIand J. Ojima, Catalytic Asymmetric Synthesis, VCH Publishers, N.Y.(1994), Chap. I.

The L13 ligands are very common and commercialized, whereas those whichcontain ferrocenyl groups are either commercialized (such is the casefor example of the compound of structure L10 wherein R represents aphenyl radical), or they can be prepared by methods analogous to thosedescribed for example by M. D. Rausch et al., J. Organometallic Chem.1967, 10, 127, R. A. Brown et al. 1992, 20, 2611 and G. Herberich etal., Chem. Ber. 1995, 128, 689. Moreover, some of theseferrocenyldiphosphine type ligands are novel compounds which are alsothe object of the invention. Such is the case namely of the ligands offormula (L8) wherein R¹ =trimethylsilyl and R² =isopropyl.

The ligands of the (L11) type wherein R=cyclohexyl et R'=phenyl, knownunder the designation of JOSIPHOS, can be prepared as is described by A.Togni et al., J. Amer. Chem. Soc. 1994, 116, 4062. They are alsocommercially available, and the same applies to their analogues (origin:STREM Chemicals, Inc.).

The above-mentioned acids of formula HX, used for the preparation of thecatalysts of the invention, are typically used in the form of thecorresponding etherates (for example HBF₄.R₂ O, R═CH₃ or C₂ H₅) or ofany other onium type salt (phosphonium or sulfonium, for example). Theseetherates are commercial products, or they can be prepared from thecorresponding silver salts, by reacting with HCl. In the latter case,the silver salt, for example AgBF₄, AgPF₆, AgSbF₆ or AgAsF₆ will betypically reacted with HCl, in a solvent containing a dialkylether, forexample a mixture of dichloromethane and diethylether. As the silverchloride precipitates, it provides the etherate solution of the acid,with is then used according to the invention in the reaction with theruthenium complex and the phosphine ligand.

Thus, as the HX acid, one can cite an acid selected from the groupconsisting of HBF₄, HPF₆, HSbF₆, HAsF₆, and HB 3,5-(CF₃)₂ C₆ H₄ !₄. Allthese acids have as common characteristic the fact that their anion isnon-coordinating.

According to a preferred embodiment of the catalyst of the invention,there is used tetrafluoroboric acid etherate.

The reaction which characterizes the process for the preparation of theinvention's catalysts takes place in a non-coordinating or weaklycoordinating medium, under inert atmosphere. By the latter, one meanshere an atmosphere whose oxygen content is lower than 200 ppm and,preferably, not above 5 to 10 ppm.

By non-coordinating or weakly coordinating medium, it is meant here forexample, a non-coordinating or weakly coordinating solvent. It may alsobe meant moreover that the reaction occurs in a solvent as definedabove, but also in the presence of the above-cited substrate of formula##STR7## wherein R¹ represents a linear or branched C₁ to C₄ alkylradical and R² represents a saturated or unsaturated, linear orbranched, C₁ to C₈ hydrocarbon radical.

It has yet been ascertained that useful catalysts could also be obtainedin the absence of the solvent, i.e. in the presence of the substrate offormula (II) alone. We observed that, surprisingly, the presence of saidsubstrate also allowed the formation of Ru(II) dicationic species whichwere themselves capable of catalyzing the hydrogenation of theabove-mentioned products (II) under the conditions which are the objectof the present invention and which will be described in detailhereafter.

When the treatment of the Ru(II) complex and the diphosphine ligand,which may be a chiral one, with the HX-acid is carried out in a solvent,the latter will be preferably selected from the group consisting ofdichloromethane, dichloroethane, ethyl pivalate, methyl acetate, ethylacetate, isopropyl acetate, acetone, 2-butanone, 3-pentanone and anymixture of two or several of these solvents.

According to a preferred embodiment, dichloromethane or a mixture of thelatter with other, non-coordinating or weakly coordinating solvents, inparticular those mentioned above, is used.

It should be pointed out that the use of the coordinating solvents whichare typically employed in the preparation of the prior art catalysts didnot make it possible to obtain catalysts which, in the course of theirapplication in the hydrogenation of the appropriate substrate (II), arecapable of providing essentially the above-mentioned preferred isomer ofHedione®, as is clearly evident from the examples given below. This,unlike what we could observe with the catalysts of the presentinvention.

Now, the structure of the dicationic complexes of Ru(II) according tothe present invention is not known. Without wanting to prejudge theirexact structural nature, it seems nevertheless quite probable that theyobey a formula of the type (diene)Ru(P*--P*)S₂ !²⁺ (anion⁻)₂, whereinthe ligand S represents the solvent (for example CH₂ Cl₂ and/or ether),the substrate or a mixture of both, and P*--P* represents a bidentatephosphine ligand, which may be chiral. In fact, given the weakelectron-donor character of the solvent and/or of substrate (II), andconsidering what is known from the prior art, it is totally surprisingto observe the formation and any hydrogenation activity of thesecatalysts, when the coordination structure around the metal cannot beentirely defined on the basis of the general knowledge in the art, byanalogy to the catalysts which have been prepared according to the knownmethods.

These new catalysts proved of excellent efficiency there where thecatalysts which had been prepared according to the methods described inthe prior art failed. We found, in fact, that their use for thehydrogenation, as the case may be asymmetric, of the compounds offormula (II) made it possible to obtain isomers of the compounds offormula ##STR8## in which R¹ and R² have the meaning indicated above,essentially in a cis configuration and, optionally, in anenantioselective manner, as a function of the chirality of the catalyst,and with excellent optical purity.

More particularly, we were able to obtain methyl(+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate with a cis purityabove 98% and an enantiomeric excess of at least 60%.

Among these catalysts, and as is apparent from the examples presentedfurther on, those which were obtained starting from the complex offormula (COD)Ru(2-methallyl)₂ ! and the (-)-Me-DuPHOS or (-)-JOSIPHOSligand, using HBF₄ -etherate in a medium of dichloromethane, or itsmixtures with methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate, proved tobe particularly advantageous for the preparation of (+)-cis-Hedione®.

The catalysts comprising the chiral ligands previously cited proved tobe particularly useful for the preparation of optically active compoundsof formula (I), in particular of methyl(+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate.

Of course, the use of the enantiomers of the above-cited ligands enablesthe preparation of the (-)-(1S)-configuration enantiomer of methylcis-3-oxo-2-pentyl-1-cyclopentane-acetate, as the optical configurationof the catalyst determines that of the hydrogenation product ofsubstrate (II).

According to the invention, the preparation of the catalyst can takeplace at room temperature or a lower temperature. Moreover, thetemperature of the above-mentioned treatment does not seem to be acritical parameter of the process, susceptible of affecting thecatalyst's properties and its efficiency in the hydrogenation of thesubstrates (II). The application of room temperature is of courseadvantageous from a practical point of view.

On the other hand, we observed that the ratio between the molecularweight of the HX acid, for example HBF₄, HPF₆, HSbF₆ ou HAsF₆, and themolecular weight of the ruthenium complex is a critical parameter whichdetermines the catalyst's characteristics and its efficiency in theasymmetrical hydrogenation of the above-mentioned substrates accordingto the present invention, and more particularly of methyl3-oxo-2-pentyl-1-cyclopentene-1-acetate. This is all the more surprisingin that the prior art is totally silent on this subject. Actually, knownstudies often report the use of a substantial excess of acid, relativeto the amount required to form the cationic ruthenium complex in thepresence of the bidentate phosphine ligand.

Now, we have ascertained that the use of an excess of acid renders thecatalysts inactive or inefficient in the context of the presentinvention. As is apparent from the examples below, it may even prove tobe advantageous to use the acid in a ratio which is inferior to thestoechiometric amount. Thus the acid will be preferably used in a ratiofrom 1.5 to 2 mole equivalents, per mole of the Ru(II) complex. Morepreferably, the ratio between these two reagents will be about 2 moleequivalents of acid per mole of complex.

Likewise, the equimolar ratio between the appropriate Ru(II) complex andthe bidentate diphosphine also seems a critical parameter of theinvention.

The invention also concerns a process for the preparation of Ru(II)catalysts, characterized in that equimolar amounts of an appropriateRu(II) complex and a bidentate diphosphine ligand are reacted, under aninert atmosphere and in a non-coordinating or weakly coordinatingmedium, with an acid of formula HX, wherein X is a non-coordinatinganion, the acid being employed in a ratio which does not exceed 2 molarequivalents per mole of Ru(II) complex.

As previously mentioned, the appropriate Ru(II) complexes, and inparticular the preferred complex (COD)Ru(2-methylallyl)₂ !, which areused as starting products in the process for the preparation of thecatalysts according to the present invention, are typically knowncompounds which can be prepared as is described in the above-cited priorart documents, or by processes which are analogous to those known.

On the other hand, the phosphines which form the ligands of the catalytsaccording to the present invention, and which determine their chirality,are either commercially available compounds or can be prepared by knownmethods.

As cited above, the preparation of the catalyst can be executed in amedium which is constituted by a solvent or a mixture of the solventwith the substrate (II). This last embodiment, as well as that accordingto which the catalyst is prepared in the presence of only the substrate(II), are methods particularly suitable for the in situ preparation ofthe catalysts, in the medium of the hydrogenation reaction, describedfurther on.

The catalysts according to the present invention thus prepared areobtained as solutions in the solvent and/or the substrate (II) of theproduct which is the result of the reaction of the Ru(II) complex withthe diphosphine ligand and the HX acid. These catalytic solutions may beused as such for the asymmetric hydrogenation of substrates (II). Theycan be kept under an inert atmosphere and will stay active for severaldays. Moreover, they may also be concentrated under vacuo to give thecatalysts in a solid form.

The catalysts can also be generated in situ in the hydrogenation medium,as will become apparent below.

In this process, the order in which the reagents are mixed does not seemto have a critical impact on the properties of the resulting catalysts.Thus, we found that it was possible to first mix the Ru(II) precursor,for example (COD)Ru(2-methallyl)₂ !, with the diphosphine ligand, inparticular (-)-Me-DuPHOS, in a solvent, typically dichloromethane, andadd thereafter to this mixture the selected acid, for example HBF₄ (inthe form of its etherate), optionally dissolved in dichloromethane.Catalytic solutions according to the present invention are thusobtained, having a variable concentration in the catalyst according tothe present invention, for example of the order of 0.01M (0.01 moles ofcatalyst/1 of catalytic solution), which proved to be very advantageousin the hydrogenation of substrates (II).

Alternatively, very good catalysts were also obtained by first mixingthe diphosphine ligand, in particular (-)-Me-DuPHOS, with the acid offormula HX, in the form of an etherate or an onium salt, in particularHBF₄ -etherate, for example in dichloromethane. The product thusobtained may be reduced to the form of a solid onium salt by removingunder vacuo the ether and CH₂ Cl₂, and thereafter be used in thereaction with the Ru(II) complex in a solvent to give the desiredcatalysts. This embodiment is quite useful in practice, as it allowsseparate preparation of the salts of the ligands, which thereafter canreact with the Ru(II) complex.

The dicationic compounds of Ru(II) according to the invention prove tobe very useful as catalysts in hydrogenation reactions. In particular,they show an excellent efficiency in the conversion of substrates (II),and the invention therefore also concerns a process for the preparationof a compound of formula ##STR9## in which R¹ represents a linear orbranched alkyl radical from C₁ to C₄ and R² represents a saturated orunsaturated hydrocarbon rest, linear or branched, from C₁ to C₈,essentially in the form of an isomer of cis configuration, characterizedin that a substrate of formula ##STR10## in which R¹ and R² have themeaning indicated above, is catalytically hydrogenated in the presenceof a Ru(II) catalyst according to the present invention as previouslydescribed, and at a hydrogen pressure of from 10 to 100 bar (2 to 10×10⁶Pa).

According to a preferred embodiment of the invention, the catalyst isgenerated in situ before the hydrogenation of substrate (II) or,optionally, in the presence of the latter, by treating equimolar amountsof the Ru(II) complex, in particular the compound of formula(COD)Ru(2-methylallyl)₂ !, and an appropriate chiral bidentate phosphineligand, selected, for example, from the group consisting of thediphosphines which are known under the abbreviations of Me-DuPHOS,Et-DuPHOS, BINAP, To1BINAP, SKEWPHOS, DIPAMP, CHIRAPHOS and JOSIPHOS,with the etherate of tetrafluoroboric acid in a proportion of about 2molar equivalents of HBF₄ per mole of Ru(II) complex. This preferredembodiment enables the preparation of the above-mentioned compound (I)in the form of an optically active isomer of (1R)-cis configuration.

All the racemic or achiral ligands mentioned above provide catalystswhich make it possible to obtain the compounds (I) in the form of theracemic cis-isomer. Of course, in the case of racemic ligands (forexample L8 and L9), their corresponding enantiomers can be obtained byseparation of the racemic ligand, and these enantiomers of the ligandmay thereafter serve to prepare optically active catalysts according tothe invention.

When the preparation of the catalyst takes place in the absence ofsubstrate (II), it is preferred to first prepare the mixture of theRu(II) complex and the diphosphine ligand, as a solution in anon-coordinating or weakly coordinating solvent, and to add to thissolution the acid comprising the non-coordinating ion, in particular theetherate of tetrafluoroboric acid, generally in the same solvent or inanother solvent with the same characteristics. The catalytic solutionthus obtained will then be used in the hydrogenation of substrate (II).

When a hydrogenation medium which comprises a solvent is used,preferably the same solvent as that in which the catalyst has beenobtained is used. For this purpose, one can use a chlorinatedhydrocarbon like dichloromethane, dichlororethane or a mixture of both.The use of dichloromethane, optionally in a mixture with the othersolvents which have been cited above, has proved to be very advantageousaccording to the invention.

According to a particularly preferred embodiment of the processaccording to the present invention, methyl3-oxo-2-pentyl-1-cyclopentene-1-acetate is used as a substrate in orderto obtain Hedione® in the form of the preferred (+)-cis-configurationisomer.

The catalysts according to the present invention which have ligands ofthe DuPHOS type, and in particular Me-DuPHOS, have proved to beparticularly useful for the hydrogenation of this substrate.

The hydrogenation which characterizes the process according to theinvention is carried out under a hydrogen pressure which can vary from10 to 100 bar (2 to 10×10⁶ Pa). Pressures from 70 to 100 bar, inparticular from 90 to 100 bar, are preferred.

The reaction may take place at temperatures of up to 50° to 60° C., oreven 100° C. Preferably, one will work at room temperature or a lowertemperature. It has been found that temperatures of down to -10° C., oreven lower, made it possible to obtain very useful results.

The molar concentrations of the Ru(II) catalyst with respect to thesubstrate typically vary from 0.01 to 4 mole %, preferably from 0.1 to 2mole %. According to a more preferred embodiment, they shall be of theorder of 0.3 or 0.4 mole %.

Moreover, it has also been found that it is advisable to use solutionsin which the substrate is concentrated, better results having beenobtained when the concentration of the substrate in the hydrogenationmedium was from about 0.4 to 1.5 molar, relative to the volume of saidmedium.

It is also possible to add a trialkylamine, preferablydiisopropylethylamine (DIPEA), to this medium. It has in fact beenobserved that, under certain conditions, the hydrogenations carried outin the presence of the latter provided more useful results. Theconcentration in which this base may be added to the reaction mediumvaries in a molar ratio of from 0.1:1 to 0.5:1, relative to the Ru(II)catalyst. The best yields of final product were obtained whendiisopropylamine was added in a proportion of 0.2 equivalents withrespect to the catalyst.

According to a particular embodiment of the hydrogenation processaccording to the invention, in which the catalyst is formed in situ inthe hydrogenation medium, the substrate which is to be hydrogenated isfirst mixed with the equimolar mixture of (COD)Ru(2-methylallyl)₂ ! anddiphoshine ligand, optionally in a solvent, and thereafter HBF₄-etherate or another salt of a HX acid is added to the thus obtainedsolution, in the proportion mentioned above. The thus obtained reactionmedium is thereafter pressurized under hydrogen in a conventionalmanner, as will be described in the examples below. This etherate oranother salt of the onium type can be added as such or in the form of asolution, and either in the same solvent as that previously used, or ina different solvent.

The invention thus provides new catalysts and processes for the use ofthese catalysts which allow the preparation, in a single step, and underconditions which are advantageous and susceptible of industrialapplication, of products useful in perfumery, in a stereoselectivemanner and, as the case may be, enantioselective, and in excellentyields. Unlike the prior art catalysts, the catalysts of the presentinvention are capable of hydrogenating substrates (II) with very fastreaction speeds, substrate conversion rates above 98% and providingessentially the diastereomer of (1R)-cis configuration of the desiredcompounds.

The invention will now be described in greater detail by means of thefollowing examples, in which the temperatures are indicated in degreescentigrade (°C.) and the abbreviations have the meaning generallyrecognized in the art.

EMBODIMENTS OF THE INVENTION EXAMPLE 1

Preparation of the catalysts

General Method

In a glove box under argon, at room temperature, a Schlenk tube wascharged with equimolar amounts of (COD)Ru(2-methylallyl)₂ ! or anothercomplex of Ru, and the selected ligand. The dried and degassed solventnecessary to dilute this mixture was added. After 5 minutes,tetrafluoroboric acid etherate (or another onium salt), optionally insolution in the non-coordinating solvent, was added dropwise using asyringe, while the mixture was stirred using a Teflon® covered magneticstirring rod. After stirring, a small amount of solvent was furtheradded and stirring was maintained for about half an hour. The catalystthus obtained in the form of a solution can be stored for several daysin the glove box without losing its activity.

The solution may also be concentrated under vacuo to provide thecatalyst in a solid form.

In a typical run, 0.20 mmole (64 mg) of (COD)Ru(2-methylallyl)₂ !(origin: Acros Organics) and 0.20 mmole (61 mg) of (-)-(R,R)-Me-DuPHOSor (-)-1,2-bis-(2R,5R)-2,5-dimethylphospholano)-benzene; origin: StremChemicals! were reacted in 4 ml of CH₂ Cl₂. A 0.10N solution (4 ml) ofHBF₄.Et₂ O (Et=ethyl; 0.40 mmole) in CH₂ Cl₂ was added. After stirringfor 30 min, another 8 ml of CH₂ Cl₂ were added, and stirring wascontinued for half an hour. The catalyst thus obtained was used as suchin the hydrogenation reactions.

Optically active catalysts were thus prepared with the followingligands: (+)-(S,S)-Me-DuPHOS; (-)-(R,R)-Me-DuPHOS; (+)-(S,S)-Et-DuPHOS;(-)-(R,R)-Et-DuPHOS; (+)-(R)-BINAP; (-)-(S)-BINAP; (-)-(R,R)-NORPHOS;(-)-(S,S)-CHIRAPHOS; (+)-(R,R)-CHIRAPHOS; (-)-(S,S)-SKEWPHOS;(+)-(R,R)-SKEWPHOS; (-)-(R,R)-DIPAMP; (+)-(S,S)-DIPAMP;(-)-(S)-To1BINAP; (+)-(R)-To1BINAP; (-)-(R)-(S)-JOSIPHOS et(+)-(S)-(R)-JOSIPHOS. All of these ligands are commercially available orare prepared according to known methods.

Other catalysts which were prepared according to the method describedabove comprised ligands of the type L7 (R=methyl, ethyl or isopropyl),L8 R¹ =(CH₃)₃ Si and R² =phenyl or isopropyl!, L9 (R¹ =CH₃ and R²=phenyl), L10 (R=ethyl, isopropyl or phenyl), L11 (R=cyclohexyl andR'=phenyl), L12 (R=phenyl) and L13 (n=1, 2, 3 or 4).

The ligands L13 mentioned above are commercially available (origin:Fluka Chemie and Aldrich), as is the ligand of type L12 cited above(origin: Strem Chemicals). The above mentioned ligands of the L8, L9 andL10 type were prepared according to known methods (see references citedabove and I. R. Butter et al., Synth. React. Inorg. Met. -Org. Chem.1985, 15, 109) from ferrocene and according to the following reactionschemes: ##STR11##

For the preparation of the ligands of type L7, one can use, for example,the method described in U.S. Pat. No. 5,171,892.

In the method of preparation of the catalyst described above, a solutionof HBF₄.Et₂ O in diethyl ether (0.2M) was also used, giving similarresults.

EXAMPLE 2

Hydrogenation of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate

General method of hydrogenation

In a glove box under argon and at room temperature, a glass beakeradapted for use in an autoclave was charged with the catalyst solutionobtained as described in example 1, the above-mentioned substrate whichhad been prior degassed, and the degassed solvent. The beaker containinga stirring rod was introduced in the autoclave inside the glove box, andthe autoclave was sealed before being taken out of the glove box to bepressurized. The inlets of the autoclave were purged with H₂ andthereafter pressurized to the chosen value. The reaction was allowed tooccur at room temperature. The pressure was released under air, theautoclave was opened and the solution concentrated under reducedpressure. The catalyst was precipitated with pentane, filtered and thefiltrate was concentrated to provide the desired Hedione®. The productcan be purified by distillation in a bulb-to-bulb apparatus (150°-200°C./5 Pa) without changing the diastereomeric ratio.

In a typical run, for example, there was used a H₂ -pressure of 90 bar(9×10⁶ Pa), room temperature and a reaction time of 1.5 h for asubstrate weight of 269 mg (1.20 mmole) and 1 ml of CH₂ Cl₂, thecatalyst being present at a ratio of 1 mole % relative to the substrate(1.0 ml of a solution of the (-)-(R,R)-Me-DuPHOS catalyst specificallydescribed in example 1).

Table I below gives a summary of the results of the different runs whichwere carried out under various conditions and with catalysts which hadbeen prepared as described in example 1, by means of the chiral ligandsindicated in table I.

Replacing the ligands mentioned in this table by their respectiveenantiomers enabled the preparation of products in which the cis/transratio was identical to the value indicated in the table for theenantiomer in question, but wherein the ratio (+)-(cis)/(-)-cis and(-)-trans/(+)-trans was the reverse of that indicated in the table.

An analysis of this table shows that when using coordinating solventssuch as methanol (runs 1 and 2) or yet mixtures of coordinating andnon-coordinating solvents, either a bad yield in Hedione® or anunfavorable cis/trans ratio is obtained, in comparison with those runswhich were carried out in, for example, dichloromethane. Moreover, whenthe substrate is too diluted (run 7), no hydrogenation is observed.

                                      TABLE I    __________________________________________________________________________                                                              Enantio-                  Catalyst                       Substrate              Yield     Enantio-                                                              meric                  concentra-                       concentra-                            Reaction                                 Solvent and                                         H.sub.2                                              of    Isomer                                                        meric ratio                  tion tion time other   pressure                                              Hedione ®                                                    ratio                                                        ratio (-)trans/    Run       Ligand     (mole %)                       (M)  (h)  conditions                                         (10.sup.6 Pa)                                              %     cis/trans                                                        (+)cis/(-)cis                                                              (+)trans    __________________________________________________________________________    1  (-)-Me-DuPHOS                  2    0.45 96   MeOH/THF (3/1)                                         9    55    9:91                                                        80:20 80:20    2  (-)-Et-DuPHOS                  2    0.45 96   MeOH/THF (3/1)                                         9    88    7:93                                                        77:23 77:23    3  (-)-Me-DuPHOS                  2    0.53 0.5  CH.sub.2 Cl.sub.2                                         9    99    97:3                                                        80:20 61:39    4  (-)-Me-DuPHOS                  1    0.53 1.5  CH.sub.2 Cl.sub.2                                         9    99    98:2                                                        80:20 60:40    5  (-)-Me-DuPHOS                  1    0.53 16.5 T = -10° C.                                         9    99    98:2                                                        86:14 60:40                                 CH.sub.2 Cl.sub.2    6  (-)-Me-DuPHOS                  1    0.53 3.25 CH.sub.2 Cl.sub.2                                         4.5  80    98:2                                                        80:20 53:47    7  (-)-Me-DuPHOS                  1    0.04 68   CH.sub.2 Cl.sub.2                                         9    6.5   60:40                                                        68:32 51:49    8  (-)-Me-DuPHOS                  0.5  0.79 5    CH.sub.2 Cl.sub.2                                         9    99    98:2                                                        80:20 58:42    9  (-)-Me-DuPHOS                  0.25 1.18 16   CH.sub.2 Cl.sub.2                                         9    99    96:4                                                        80:2()                                                              67:33    10 (-)-Me-DuPHOS                  2    0.37 15   toluene-CH.sub.2 Cl.sub.2                                         9    4.5   45:55                                                        --    --                                 (1:2)    11 (+)-(R,R)-SKEWPHOS                  2    0.53 3    CH.sub.2 Cl.sub.2                                         10   24    95:5                                                        75:25 58:42    12 (-)-(S,S)-CHIRAPHOS                  2    0.53 2    CH.sub.2 Cl.sub.2                                         9    97    96:4                                                        31:69 --    13 (-)-(R,R)-NORPHOS                  2    0.53 2    CH.sub.2 Cl.sub.2                                         9    98    96:4                                                        57:43 --    14 (+)-(S,S)-DIPAMP                  2    0.53 2    CH.sub.2 Cl.sub.2                                         9    50    94:6                                                        69:31 --    15 L7 (R = CH.sub.3)                  2    0.53 12   CH.sub.2 Cl.sub.2                                         5    98    97:3                                                        67:33 --    16 L7 (R = C.sub.2 H.sub.5)                  2    0.53 12   CH.sub.2 Cl.sub.2                                         5    89    98:2                                                        73:27 --    17 L7 (R = isopropyl)                  2    0.53 12   CH.sub.2 Cl.sub.2                                         5    97    97:3                                                        73:27 --    18 LII (R = cyclohexyl                  2    0.50 4.5  CH.sub.2 Cl.sub.2                                         9    98    98:2                                                        77:23 --       R' = phenyl))    __________________________________________________________________________

EXAMPLE 3

The substrate mentioned in example 2 was hydrogenated according to amethod analogous to that described above, by proceeding as follows.

In a glove box under argon and at room temperature,(COD)Ru(2-methylallyl)₂ ! (16.5 mg; 0.051 mmole) was dissolved indichloromethane (1 ml) and stirred for 2 min. To the resulting solution,a solution of (+)-R-BINAP (+)-(R)-2,2'-bis(diphenylphosphino-1,1'-binaphtalene); 31.6 mg; 0.051 mmole; origin:Fluka Chemicals! in dichloromethane (2 ml) was added and stirred forabout 30 min. Then tetrafluoroboric acid etherate (14 μl; origin: FlukaChemie) was added. Having stirred for 30 min, a solution of methyl3-oxo-2-pentyl-1-cyclopenteneacetate (0.5 g; 2.23 mmole) indichloromethane (10 ml) was added and stirred for 30 min at roomtemperature. This solution, still under Ar, was charged in an autoclavewhich contained a glass beaker with a magnetic stirrer. After purgingwith H₂, the autoclave was pressurized at 9×10⁶ Pa for 64 h at 20° C.After decompressing the orange solution was taken and concentrated underhigh vacuo. The residue was taken in pentane (2 ml) to precipitate thecatalyst. The solution was filtered on a 0.45 μm acrodisc andconcentrated. 500 mg of a transparent oil containing 93% Hedione®, witha cis/trans ratio of 72:28, and 6% of starting product were thusobtained. The enantiomeric ratios were as follows:(+)-cis/(-)-cis=73/27; (+)-(trans)/(-)-trans=35/65.

EXAMPLE 4

In a glove box under argon and at room temperature, 5.376 g (24 mmole)of the substrate cited in the above examples, 19.2 mg of(COD)Ru(2-methylallyl)₂ ! (0.06 mmole), 0.06 mmole (18.4 mg) of(-)-Me-DuPHOS and 12 ml of CH₂ Cl₂ were charged into a glass beakeradapted for use in an autoclave and equipped with a stirrer. Thereafter,0.12 mmole of HBF₄ etherate (1.2 ml of a 0.1N solution indichloromethane) were added. After stirring for 1 h, the beakercontaining a stirring rod was introduced in the autoclave inside theglove box, and the autoclave was closed before being pressurized outsidethe glove box. The inlets of the autoclave were purged with H₂ andthereafter pressurized at 2×10⁶ Pa. The reaction was allowed to proceedat room temperature for 17 h. The autoclave was degassed and opened andthe solution concentrated under reduced pressure. The catalyst wasprecipitated with pentane, filtered and the resulting filtrateconcentrated to obtain the desired Hedione®. The product thus obtained(yield 99%) showed the following isomer ratios: cis/trans=97/3 ;(+)-cis/(-)-cis=80/20.

EXAMPLE 5

The reaction was carried out in a similar manner to that described inexamples 2 to 4, but 2.2 equivalents of tetrafluoroboric acid (from a0.2M solution. of HBF₄ etherate in diethyl ether) per mole of Ru(II)complex were used in the preparation of the catalyst which was carriedout analogously to the way described in example 1.

Moreover, in the runs which are summarized in the tables below, thecatalyst was used in solid form. Thus, methyl3-oxo-2-pentyl-1-cyclopentene-1-acetate (0.5 mmole in 2 ml of CH₂ Cl₂)was hydrogenated in the presence of the amount of solid catalystindicated in the tables.

Table II below summarizes the results which were obtained in thehydrogenation reactions carried out with different catalysts (variationof the nature of the ligand) in the concentrations indicated, a hydrogenpressure of about 100 bar (10×10⁶ Pa), room temperature and a reactiontime of about 22 h.

Table III summarizes the results which were obtained with differentcatalysts (variation of the nature of the ligand) and by varying severalreaction parameters. All reactions were carried out at room temperature,unless otherwise indicated.

                                      TABLE II    __________________________________________________________________________                              Yield               Catalyst       of    Isomer                                        Enantiomeric                                              Enantiomeric               concentration  Hedione ®                                    ratio                                        ratio ratio    Run       Ligand  (mole %)                      Solvent %     cis/trans                                        (+)cis/(-)cis                                              (-)trans/(+)trans    __________________________________________________________________________    1  (-)-Me-DuPHOS               2      MeOH    31    32:68                                        80:20 78:22    2  (-)-Me-DUPHOS               2      MeOH +  9.1   72:28                                        65:35 54:46                      triethylamine*    3  (-)-Me-DUPHOS               2      triethylamine** +                              4.5   68:32                                        55:45 41:59                      MeOH    4  (-)-Me-DuPHOS               2      THF     5.5   61:39                                        63:37 56:44    5  (-)-Me-DuPHOS               2      CH.sub.2 Cl.sub.2                              100   82:18                                        80:20 77:23    6  (-)-Et-DuPHOS               1      CH.sub.2 Cl.sub.2                              77    80:20                                        70:30 73:27    7  (+)-BINAP               1      CH.sub.2 Cl.sub.2                              77    74:26                                        71:29 65:35    8  (-)-Me-DUPHOS               1      CH.sub.2 Cl.sub.2                              91    79:21                                        79:21 77:23    __________________________________________________________________________     *1 equivalent per mole of catalyst     **2 equivalents per mole of catalyst

                                      TABLE III    __________________________________________________________________________                Catalyst              Yield Iso-                concentra-                     Reaction     H.sub.2                                      of    meric                                                Enantiomeric                                                      Enantiomeric                tion time         pressure                                      Hedione ®                                            ratio                                                ratio ratio    Run       Ligand   (mole %)                     (h)  Solvent (10.sup.6 Pa)                                      %     cis/trans                                                (+)cis/(-)cis                                                      (-)trans/(+)trans    __________________________________________________________________________    1  (-)-Me-DuPHOS                1.0  14.5 CH.sub.2 Cl.sub.2                                  10  93    94:6                                                80:20 72:28    2* (-)-Me-DUPHOS                4.0  6.0  CH.sub.2 Cl.sub.2                                  9   90    86:14                                                83:17 79:21    3  (-)-Me-DuPHOS                1.0  40.0 CH.sub.2 Cl.sub.2                                  10  95    75:25                                                79:21 77:23    4  (-)-Me-DuPHOS                1.0  40   CH.sub.2 Cl.sub.2 +                                  10  95    82:18                                                79:21 76:24                          DIPEA.sup.a) (0.2 eq.)    5  (-)-Me-DuPHOS                2.0  2    CH.sub.2 Cl.sub.2+                                  9   43    96:4                                                80:20 56:44                          DIPEA.sup.a) (1.0 eq.)    6  (-)-Me-DuPHOS                2.0  2    CH.sub.2 Cl.sub.2 +                                  9   2,1   59:41                                                46:54 60:40                          DIPEA.sup.a) (2.0 eq.)    7**       (-)-Me-DuPHOS                2.0  2    CH.sub.2 Cl.sub.2 +                                  9   98    97:3                                                81:19 64:36                          DIPEA.sup.a) (0.2 eq.)    8  (-)-(R,R)-DIPAMP                2.0  2    CH.sub.2 Cl.sub.2 +                                  9   50    94:6                                                31:69 52:48                          DIPEA.sup.a) (0.2 eq.)    9  (-)-(S)-TolBINAP                2.0  2    CH.sub.2 Cl.sub.2 +                                  8   88    96:4                                                31:69 48:52                          DIPEA.sup.a) (0.2 eq.)    __________________________________________________________________________     .sup.a) diisopropylethylamine     *Temperature 0-5° C.     **Substrate degassed before hydrogenation

EXAMPLE 6

In a glove box under argon and at room temperature, 38 mg of(COD)Ru(2-methylallyl)₂ ! (0.12 mmole) and 36 mg (0.12 mmole) of(-)-Me-DuPHOS were dissolved in 5.38 g (24 mmole) ofmethyl-3-oxo-2-pentyl-1-cyclopentene-acetate in a glass beaker adaptedfor use in an autoclave which was equipped with a stirrer. Thereafter,39 mg of HBF₄ etherate (0.24 mmole; 32.7 μl, syringe) were gently addedunder stirring. After stirring for 4 h, 3.4 ml of this catalyticsolution (containing about 0.075 mmole of catalyst) were transferred toanother beaker, and another 8.38 g (37.4 mmole) of methyl3-oxo-2-pentyl-1-cyclopentene-1-acetate (total amount about 53 mmole)were added to this. Working as previously described, the substrate washydrogenated at a H₂ pressure of 5×10⁶ Pa. The reaction was allowed toproceed for 20 h at room temperature. The autoclave was degassed,opened, and the catalyst was precipitated using pentane, filtered andthe filtrate concentrated to obtain the desired Hedione®. The thusobtained product (yield 99% based on the above mentioned substrate)showed the following isomer ratios: cis/trans=97/3:(+)-cis/(-)-cis=80/20, 60% e.e.

By working under similar conditions but varying the nature of thesolvent used in the hydrogenation, i.e. of the solvent of the mixture of(COD)Ru(2-methallyl)₂ ! and (-)-Me-DuPHOS, as well as that of thesolvent of the tetrafluoroboric acid etherate, the results given in thetable below were obtained. The hydrogenated substrate (II) was alwaysmethyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate, and the catalystconcentration was about 2 mole % relative to the mentioned substrate,unless otherwise indicated.

When the tetrafluoroboric acid etherate is used in solution, itsconcentration in the solution is always about 0.1M (moles/1).

Yields of the order of 99% in Hedione®, based on starting substrate (II)present in the hydrogenation medium, were systematically obtained. Ofcourse, when ratios of catalyst/substrate of the order of 0.5 mole % orless were used, prolonged reaction times (in the range from 6 to 20 h)were necessary to obtain a complete and quantitative conversion of thesubstrate, while hydrogenation times of 1 to 3 h in general weresufficient to obtain this result when the catalyst was present inconcentrations of the order of 1 mole % or more, with respect to thesubstrate.

Every time, almost no losses were observed, only traces of residues(˜1%) being obtained when the hydrogenation product was distilled in abulb to bulb apparatus or a Leybold distillation apparatus ("thin-filmdistillation").

                                      TABLE IV    __________________________________________________________________________                            Isomer                                  Enantiomer       Hydrogenation                 Solvent for                            ratio ratio    Run       solvent   HBF.sub.4.Et.sub.2 O                            cis/trans                                  (+)-cis/(-)-cis    __________________________________________________________________________    1  dichloroethane                 dichloroethane                            99:1  70:30    2  methyl pivalate                 dichloromethane                            98.9:1.1                                  76:24    3  ethyl acetate                 dichloromethane                            99.3:0.7                                  73:27    4  isopropyl acetate                 dichloromethane                            99.3:0.7                                  72:28    5  2-butanone                 dichloromethane                            98.9:1.1                                  79:21    6  methyl acetate                 methyl acetate                            98.5:1.5                                  75:25    7  methyl acetate                 methyl     99.3:0.7                                  74:26                 acetate/dichloromethane    8  methyl acetate                 dichloromethane                            99:1  77:23    9  methyl acetate/DHH*                 methyl acetate                            98.5:1.5                                  75:25    10 acetone   dichloromethane                            99.5:0.5                                  79:21    11 DHH*      methyl acetate                            98.2:1.8                                  81:19    12 DHH*      --         98.2:1.8                                  81:19    13 3-pentanone                 dichloromethane                            98.9:1.1                                  79:21    14 tetrahydrofurane                 dichloromethane                            no hydrogenation observed    15 toluene   dichloromethane                            no hydrogenation observed    16 N-methylformamide                 dichloromethane                            no hydrogenation observed    17 N,N-dimethyl-                 dichloromethane                            no hydrogenation observed       formamide    18 sulfuric ether                 dichloromethane                            very slow reaction    19 chloroform                 chloroform no hydrogenation observed    20 methyl-2-methyl-                 dichloromethane                            very slow reaction       proponoate    21**       DHH*      --         96.7:3.3                                  80:20    __________________________________________________________________________     *methyl 3oxo-2-pentyl-1-cyclopentene-1-acetate     **catalyst concentration 0.15 mole %

EXAMPLE 7

The reaction was carried out analogously to that described in example 6,but using 100 g (446 mmole) of methyl3-oxo-2-pentyl-1-cyclopentene-acetate, 427 mg (1.34 mmole) of(COD)Ru(2-methylallyl)₂ !, 410 mg (1.34 mmole) of (-)-Me-DuPHOS and 26.5ml of HBF₄.O(C₂ H₅)₂ in dichloromethane (0.1M, 2.68 mmole). Thiscorresponds to a catalyst concentration of 0.3 mole %, relative to thesubstrate. 170 ml of dichloromethane were added, and the mixture washydrogenated at a temperature of 7.5° C. and a pressure of 5×10⁶ Pa for70 h to obtain methyl (+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetatein 99% yield, cis/trans ratio=99.2/0.8 and (+)-cis/(-)-cis ratio=84/16.

EXAMPLE 8

The catalysts according to the invention were prepared using(-)-Me-DuPHOS as ligand and varying on the nature of the acid of formulaHX.

The respective acids HBF₄, HPF₆, HSbF₆ and HAsF₆ (as etherates) wereprepared by reacting 0.2 mmole of the corresponding silver salt in 0.8ml of dichloromethane, using 0.2 ml of a 1M anhydrous solution of HCl 1Min ether.

The silver chloride formed precipitated immediately, and 1 ml of a 0.2Msolution of the respective acid, i.e. HBF₄, HPF₆, HSbF₆ or HAsF₆, wasobtained.

Thereafter, 6.4 mg of (COD)Ru(2-methylallyl)₂ ! (0.02 mmole), 6.4 mg of(-)-Me-DuPHOS (0.021 mmole) and 0.224 g of methyl3-oxo-2-pentyl-1-cyclopenteneacetate in 2 ml of dichloromethane werecharged into a reactor. The solution thus obtained was treated with 0.20or 0.16 ml (2 or 1.6 molar equivalents of ruthenium complex) of theabove-mentioned acid solution.

The mixture was thereafter hydrogenated at room temperature and 10×10⁶Pa to give the results summarized in the table below. It should benoticed that the runs were not optimized, which explains the poorresults obtained in some cases.

    __________________________________________________________________________                                          (-)-Trans/           Acid  Reaction time                        Yield of                              Cis/trans                                   (+)-Cis/(-)-cis                                          (+)-trans    Run       Acid           equivalents                 (h)    Hedione ®                              ratio                                   ratio  ratio    __________________________________________________________________________    1  HBF.sub.4           2     3      99.4  88:12                                   81:19  79:21    2  HBF.sub.4           1.6   3      98.7  87:13                                   82:18  81:19    3  HAsF.sub.6           2     3.5    78.7  56:44                                   79:21  78:22    4  HAsF.sub.6           1.6   3.5    99.3  82:18                                   78:22  78:22    5  HPF.sub.6           2     2      2.9   51:49                                   57:43  60:40    6  HPF.sub.6           1.6   2      80.8  86:14                                   71:29  69:31    7  HSbF.sub.6           2     3      98.3  48:52                                   75:25  74:26    8  HSbF.sub.6           1.6   3      99.0  84:16                                   75:25  74:26    __________________________________________________________________________

Similar results were obtained when diisopropylethylamine 0.040 ml of a0.1M solution; 20 mole % with respect to Ru(II)! was added to thehydrogenation medium. Improvement (of the order of 10%) of the cis/transisomer ratio was then observed.

EXAMPLE 9

The activity of a variety of racemic or achiral catalysts according tothe invention, prepared as described in example 1, using HBF₄ as theacid (in the form of its etherate), and varying the ligand, was testedin the hydrogenation reaction of methyl3-oxo-2-pentyl-1-cyclopentene-acetate.

All hydrogenations were carried out in dichloromethane and at roomtemperature. The results are given in the table. It should be noticedthat these runs were not optimized, which explains the poor substrateconversions observed in some cases.

    __________________________________________________________________________                     Catalyst                            Reaction                                 H.sub.2                                      Conversion                                            Isomer                     concentration                            time pressure                                      of substrate                                            ratio    Run       Ligand        (mole %)                            (h)  (10.sup.6 Pa)                                      (%)   cis/trans    __________________________________________________________________________    1  L13 (n = 1)   2      4    5    9     94:6    2  L13 (n = 2)   2      6    5    18    96.6:3.4    3  L13 (n = 3)   2      6    5    18    96.6:3.4    4  L13 (n = 4)   2      4    5    35    98.8:1.2    5  L10 (R = C.sub.6 H.sub.5)                     2      14.5 5    29    98:2    6  L10 (R = isopropyl)                     1      3    5    53    98.9:1.1    7* L10 (R = isopropyl)                     2      7.5  5    98.5  96.8:3.2    8  L10 (R = C.sub.2 H.sub.5)                     1      17   5    4     81:19    9**       L12 (R = C.sub.6 H.sub.5)                     2      25   9    96    91.3:8.2    10 L8  R.sup.1 = Si(CH.sub.3).sub.3                     2      5    5    30    98.3:1.7           R.sup.2 = C.sub.6 H.sub.5    11 L8  R.sup.1 = Si(CH.sub.3).sub.3                     2      22   9    92    97.0:3.0           R.sup.2 = isopropyl    12 L8  R.sup.1 = Si(CH.sub.3).sub.3                     1      8    4    43    98.3:1.7           R.sup.2 = isopropyl    13 L8  R.sup.1 = CH.sub.3                     2      24   9    15    94.4:5.6           R.sup.2 = C.sub.6 H.sub.5    __________________________________________________________________________     *25% of alcohols resulting from the reduction of Hedione ®     (byproducts)     **7% of alcohols resulting from the reduction of Hedione ®     (byproducts)

EXAMPLE 10

A. In a glove box under argon, 4.05 g of HBF₄.Et₂ O (Et=C₂ H₅ ; 25.0mmole, 3.40 ml) were introduced into a glass beaker using a pipette,then about 100 ml of dichloromethane were added. Thereafter the mixturewas stirred to dissolve the etherate and the beaker was filled up to avolume of 250 ml. The 0.1M (moles/1) solution of HBF₄.Et₂ O thusobtained was used as such for the preparation of the catalyst.

B. In a glove box, 16.0 mg (0.050 mmole) of Ru(COD)(2-methallyl)₂ ! and15.0 mg (0.050 mmole) of (-)-Me-DuPHOS were mixed in a glass containerand dissolved in 4 ml of CH₂ Cl₂. Thereafter, 1 ml (0.1 mmole) of theHBF₄ etherate solution prepared in step A was added slowly (about 1 min)at room temperature via a syringe. The resulting red-brown solutioncontaining about 0.01M (moles/1) of catalyst was allowed to stand for 2h before use. The solution stays active for more than 1 week when keptin the glove box at room temperature.

C. Inside the glove box, 224 mg (1 mmole) of methyl3-oxo-2-pentyl-1-cyclopentene-1-acetate were added to 2 ml of thecatalytic solution obtained in step B (0.02 mmole, 2 mole % with respectto the substrate) in a glass beaker which can be transferred to anautoclave. The solution thus obtained was then transferred into anautoclave and stirred for 2 h at 90 bar (9×10⁶ Pa) hydrogen pressure atroom temperature. The autoclave was almost entirely degassed and openedinside the glove box. The yellow-orange reaction mixture was evaporatedunder vacuo to strip the dichloromethane. The solid residue and theyellow-orange liquid thus obtained were treated with pentane and thesuspension filtered through a Teflon® filter of 0.22 μ to precipitatethe catalyst. The remaining solid was washed with pentane and filteredthrough the same filter. The combined pentane solutions contained thedesired Hedione® in a cis/trans ratio=98.5/1.5 and a ratio(+)-cis/(-)-cis=79/21.

D. A second hydrogenation cycle was carried out with the catalyst whichhad remained in the Teflon® filter. The latter was washed with 2 ml ofCH₂ Cl₂ and the same dichloromethane used to dissolve the precipitatewhich had remained in the container. 224 mg of the substrate mentionedin C were added to this solution, which was thereafter hydrogenated asdescribed in C to again obtain Hedione® with a cis/trans ratio of98.8/1.2 and a (+)-cis/(-)-cis ratio of 79/21.

B'. According to an alternative embodiment to the one described under B,the catalyst was also prepared as follows: the HBF₄.Et₂ O solution indichloromethane described under A was first added to (-)-Me-DuPHOS, andthe ether and the dichloromethane were evaporated. The thus obtainedsolid of the onium salt of the ligand was then redissolved in puredichloromethane and added to Ru(COD)(2-methallyl)₂ !. The reactionoccurs with release of isobutene. The catalyst thus obtained was usedunder conditions identical to those described under C to give(+)-cis-Hedione® having the same characteristics.

C' Results similar to those described under C were obtained whenbis(2,4-dimethylpentadienyl)ruthenium (see, for example, L. Stahl etal., Organometallics, 1983, 2, 1229) orbis(2,4-dimethyl-1-oxapentadienyl)ruthenium (see T. Schmidt et al., J.Chem. Soc. Chem. Comm., 1991, 1427) were used for the preparation of thecatalyst, instead of the complex Ru(COD)(2-methallyl)₂ !.

C". Moreover, the use in the hydrogenation described under C of acatalyst prepared in a manner identical to that described under B butusing as ligand (-)-JOSIPHOS (ligand L11, R=cyclohexyl, R'=phenyl;origin: STREM Chemicals Inc.) enabled the preparation of Hedione® with acis/trans ratio of 98/2 and a (+)-cis/(-)-cis ratio of 77/23.

EXAMPLE 11

The reaction was carried out in a way similar to that described inExamples 10A to C, but using 4.171 g (13.056 mmole) ofRu(COD)(2-methallyl)₂ !, 4.000 g (13.056 mmole) of (-)-Me-DuPHOS, 1000 g(4.458 mole) of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate, 261 ml(26.10 mmole) of the 0,1M HBF₄.Et₂ O-solution in dichloromethane and1.71 of CH₂ Cl₂.

The hydrogenation reaction was carried out at 7,5° C. and under ahydrogen pressure of 35 bar (3.5×10⁶ Pa) for 24 h, under stirring(1000-2000 rpm).

After evaporation of the solvent, 1095 g of a brown product wereobtained which were treated with pentane and the solution filtered aspreviously described. The combined pentane extracts were concentratedunder vacuo to give 978 g of product, the thin-film distillation ofwhich (Leybold type apparatus, 86°/0.1 mbar) gave 932 g of a colourlessproduct consisting of the desired Hedione® having a cis/trans ratio of98/2 and a (+)-cis/(-)-cis ratio of 85/15.

We claim:
 1. Ruthenium (II) catalyst comprising ligands formed ofbidentate phosphines, characterized in that it is obtainable by aprocess which comprises treating an appropriate Ru(II) complex and abidentate diphosphine ligand, present in equimolar amounts, with an acidof formula HX, wherein X is a non-coordinating anion, said acid beingused in a ratio which does not exceed 2 molar equivalents per mole ofthe Ru(II) complex, the treatment being carried out in anon-coordinating or weakly coordinating medium and under an inertatmosphere.
 2. Catalyst according to claim 1, characterized in that theRu(II) complex is selected from the group of Ru(II) compounds of thetype (diene)Ru(allyl)₂ or bis(pentadienyl)Ru.
 3. Catalyst according toclaim 2, characterized in that the ruthenium complex is(COD)Ru(2-methallyl)₂, bis(2,4-dimethylpentadienyl)Ru orbis(2,4-dimethyl-1-oxapentadienyl)Ru.
 4. Catalyst according to claim 1,characterized in that the diphosphine ligand is selected from the groupconsisting of the chiral ligands known under the abbreviations ofMe-DuPHOS, Et-DuPHOS, BINAP, To1BINAP, SKEWPHOS and JOSIPHOS. 5.Catalyst according to claim 4, characterized in that the bidentatephosphine ligand is selected from the group consisting of the chiraldiphosphines known under the abbreviations of Me-DuPHOS, SKEWPHOS andJOSIPHOS.
 6. Catalyst according to claim 5, characterized in that theligand is (R,R)-(-)-Me-DuPHOS.
 7. Catalyst according to claim 1,characterized in that the acid is selected from the group consisting ofHBF₄, HPF₆, HSbF₆, HAsF₆, and HB{3,5-(CF₃)₂ C₆ H₄ }₄.
 8. Catalystaccording to claim 7, characterized in that HBF₄ is used in the form ofits etherate.
 9. Catalyst according to claim 7, characterized in thatthe acid is used in a proportion of 1.5 to 2 molar equivalents per moleof Ru(II) complex.
 10. Catalyst according to claim 1, characterized inthat the treatment is carried out in presence of a non-coordinating orweakly coordinating organic solvent and/or of a substrate of formula##STR12## wherein R¹ represents a linear or branched alkyl radical fromC₁ to C₄ and R² represents a saturated or unsaturated, linear orbranched hydrocarbon rest from C₁ to C₈.
 11. Catalyst characterized inthat the treatment is carried out only in the presence of a substrate offormula (II) as defined in claim
 10. 12. Catalyst according to claim 10,characterized in that the solvent is selected from the group consistingof dichloromethane, dichloroethane, methyl pivalate, methyl acetate,ethyl acetate, isopropyl acetate, acetone, 2-butanone, 3-pentanone andany mixture of said solvents.
 13. Catalyst according to claim 12,characterized in that the solvent is or comprises dichloromethane. 14.Catalyst according to claim 10, characterized in that the substrate offormula (II) is methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate. 15.Catalyst according to claim 1, characterized in that the treatment iscarried out at room temperature.
 16. Process for the preparation of acatalyst of Ru(II), characterized in that equimolar amounts of anappropriate Ru(II) complex and of a bidentate phosphine ligand arereacted, under an inert atmosphere and in a non-coordinating or weaklycoordinating medium, with an acid of formula HX, wherein X represents anon-coordinating anion, said acid being used in a proportion notexceeding 2 molar equivalents per mole of Ru(II) complex.
 17. Processaccording to claim 16, characterized in that the reaction is carried outin the presence of an organic non-coordinating or weakly coordinatingsolvent and/or a substrate of formula ##STR13## wherein R¹ is a linearor branched alkyl radical from C₁ to C₄ and R² is a saturated orunsaturated, linear or branched hydrocarbon rest from C₁ to C₈. 18.Process for the preparation of a compound of formula ##STR14## whereinR¹ represents a linear or branched alkyl radical from C₁ to C₄ and R²represents a saturated or unsaturated, linear or branched hydrocarbonrest from C₁ to C₈, essentially in the form of the cis-configurationisomer, characterized in that a substrate of formula ##STR15## in whichR¹ and R² have the meaning indicated above, is hydrogenated in thepresence of a Ru(II) catalyst according to claims 1, at a hydrogenpressure from 10 to 100 bar.
 19. Process according to claim 18,characterized in that there is used a catalyst comprising as a ligand anappropriate chiral diphosphine, to obtain compound (I) essentially inthe form of an optically active isomer of (1R)-cis configuration. 20.Process according to claim 18, characterized in that the catalytichydrogenation is carried out in a non-coordinating or weaklycoordinating solvent under the reaction conditions.
 21. Processaccording to any of claims 18, characterized in that the Ru(II) catalystis formed in situ, optionally in the presence of the substrate offormula (II).
 22. Process according to claim 20, characterized in thatthe non-coordinating solvent is selected from the group consisting ofdichloromethane, dichloroethane, methyl pivalate, methyl acetate, ethylacetate, isopropyl acetate, acetone, 2-butanone, 3-pentanone, and anymixture of said solvents.
 23. Process according to any of claims 18,characterized in that the substrate of formula (II) is methyl3-oxo-2-pentyl-1-cyclopentene-1-acetate and in that essentially methyl(+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate is obtained. 24.Process according to claim 23, characterized in that the hydrogenationis carried out in the presence of a catalyst selected from the groupconsisting of the chiral diphosphines known under the abbreviations ofMe-DuPHOS, Et-DuPHOS, BINAP, To1BINAP, SKEWPHOS, and JOSIPHOS. 25.Process according to any of claim 18, characterized in that the catalystis present in a concentration from 0.1 to 2 mole %, with respect to thesubstrate.
 26. A catalyst prepared by the process of claim 16.